Osteoporosis is a debilitating bone disease predominantly affecting postmenopausal women. Despite recent advances, therapeutic options available for its prevention and treatment are limited. The available FDA approved therapies for osteoporosis are expensive, and some are associated with significant adverse effects. The goal of this proposed research is to establish the role of nitric oxide (NO) in the prevention of postmenopausal osteoporosis. Others and we have conducted several in vivo and in vitro studies that suggest that NO play an important role in bone homeostasis. Furthermore, administration of nitroglycerin (NG) not only prevented bone loss, but also restored lost BMD following ovariectomy in rats. Once a day administration in rats for up to 6-months, and in humans up to 1 year, did not result in tachyphylaxis. Taking together these in vitro and in vivo data, we hypothesized that NG might exert a similar beneficial effect in preventing postmenopausal bone loss. The data compelled us to carry out an intervention study to assess the efficacy of NG in humans. To effectively address this issue, we plan to conduct a randomized, double blinded, controlled clinical trial in postmenopausal women. We will screen pre-selected -1,000 postmenopausal women who fulfill clinical criteria, and recruit 195 women for this study, and then follow them up for a period of 3 years. The primary end-point of the study is the lumbar BMD, and secondary end-points are hip BMD, biomarkers and bone histomorphometry. We will randomize these patients (block randomization method) into three groups: calcium and vitamin D (control), prempro (positive control), and 22 mg of NG ointment applied once daily to skin (n=65/group). Patients will be reviewed at six-month intervals at our GCRC clinical facility and additional telephone contacts with patients will be made every two months to optimize compliance and to assess adverse effects. We have constructed a stringent safety net to protect these women's health. All variables will be assessed at the beginning and then at yearly intervals for the 3-years. We believe that this study should provide definitive data on whether NO donor, NG treatment, would be beneficial in preventing bone loss in postmenopausal women. It should, therefore, help in devising a novel cost-effective alternative therapy for estrogen to prevent postmenopausal bone loss. The study will also pave the way for the future for providing more acceptable affordable and cost-effective therapies for the prevention of postmenopausal osteoporosis.